Telomeres are important for chromosomal stability and replication, and the enzyme telomerase is important for telomere formation, maintenance, and restoration. Telomerase activity and telomere length, cell aging measures, have clinical significance for health: a growing literature has linked lower levels of telomerase activity and shorter telomeres with health behaviors, age-related diseases, and mortality. Inflammation and oxidative stress accelerate telomere shortening; oxidative stress promotes telomere erosion during cellular replication, and inflammation enhances the leukocyte turnover rate. The omega-3 (n-3) polyunsaturated fatty acids (PUFAs) can reduce inflammation and decrease oxidative stress. Accordingly, by adding cell aging studies to an ongoing NIA-funded double-blind, placebo-controlled randomized controlled trial (RCT) that addresses the impact of n-3 PUFA supplementation on inflammation and mood (R01 AG029562), this study will assess the impact of diet-related reductions in inflammation and oxidative stress on telomerase activity and leukocyte telomere length. Key preliminary data from the collaborating UCSF and OSU laboratories support both the relevance and likelihood of success. UCSF's recent large prospective study with stable coronary heart disease patients demonstrated that higher baseline n-3 PUFA levels were associated with slower telomere attrition 5 years later, and another UCSF study showed increased telomerase activity following a 3-month intervention, providing a reasonable mechanism. In accord with this finding, preliminary collaborative OSU/UCSF data from the OSU n-3 RCT show that individuals receiving n-3 supplementation had longer telomeres at the end of the four-month trial, in contrast to modest telomere shortening observed among placebo subjects, producing a significant group by time interaction. Thus, the proposed study will assess the impact of a simple dietary intervention on the cell aging process. Further, it will test specific mechanisms such as whether the n-3 PUFAs reduce cell aging through alterations in proinflammatory cytokines and/or oxidative stress. In short, the addition of cell aging assessments to the OSU RCT will leverage our well-characterized sample to simultaneously address important and innovative basic science and clinical health questions. Our primary aim is: (1) To assess the impact of n-3 PUFA supplementation on changes in telomerase activity, and secondarily, in telomere length, as well as the relationship of these changes to n-3 dose. Secondary Aims: (2) To determine if changes in proinflammatory cytokines and oxidative stress mediate the effect of n-3 supplementation on cell aging; (3) to replicate and extend prior reports of cross-sectional relationships between telomerase activity and telomere length with proinflammatory cytokines and depressive symptoms; and (4) To replicate recent evidence showing that a laboratory stressor increases telomerase responsivity, and to explore how telomerase responsivity to acute stress may be altered by n-3 supplementation. PUBLIC HEALTH RELEVANCE: Telomerase activity and telomere length, cell aging measures, have clinical significance for health. Lower levels of telomerase activity and shorter telomeres are associated with aging, age-related diseases, and mortality. Preliminary data suggest that higher blood levels of omega-3 fatty acids may serve to slow age- related telomere attrition. By adding cell aging assessments to an ongoing randomized controlled trial of omega-3 supplementation, we can assess how omega-3 supplementation affects both telomerase activity and telomere length, as well as possible mechanisms.